The proposed research will examine mechanisms underlying links between psychosocial stress and health outcomes as individual's age. Tapping into an existing longitudinal dataset, the propose research will test whether, when, and how exposure to different types of stress early in life statistically interact with life stress in adulthood to predict negative health outcomes. We predict that individuals exposed to higher levels of physical and/or social stress early in life will: (a) be more stress-reactive in response to difficult/challenging situations in adulthood (i.e., hyper HPA-axis reactivity, indexed by daily and event- elicited cortisol levels), (b) have greater inflammation (indexed by levels of C-reactive protein/interleukin-6), and (c) report more health problems in adulthood. These outcomes should be most pronounced when "vulnerable" individuals (those who experienced more stress early in life) encounter higher levels of stress in adulthood, with greater early life stress statistically interacting with greater current life stress to forecast more negative cortisol, inflammation, and health outcomes. We will also test whether and how the quality of caregiving and social support earlier in life moderates (strengthens or weakens) relations between early life stress and adult health outcomes. The results should facilitate the development of interventions designed to prevent vulnerable individuals from experiencing negative health outcomes in adulthood. PUBLIC HEALTH RELEVANCE: The proposed research will examine mechanisms underlying relations between psychosocial stress and health outcomes as individuals age across time. One of the boldest hypotheses in medicine is that many medical conditions are not merely reactions to immediate pathogenic factors;they are potentiated by early experience. Early life stress may be one primary mechanism of transmission. According to this viewpoint, exposure to chronic stress early in life may "program" or sensitize certain biological systems, making them more reactive to social and environmental demands later in life and rendering these individuals more vulnerable to negative health outcomes. Although these programming effects can be long-lasting, they are potentially reversible. The proposed study will test this developmental hypothesis using more than 30 years of prospective longitudinal data from a high-risk sample of participants from the Minnesota Study of Risk and Adaptation (Sroufe, Egeland, Carlson, &Collins, 2005). The primary goals are: (1) to better understand the mechanisms by which early life stress increases adult health risks, (2) to identify specific stressors and especially the timing of their influence on adult risk processes, and (3) to identify specific moderating variables such as early caregiving quality and relationship support that could guide prevention/ intervention efforts. Understanding these health- related trajectories may not only impact medical practice;it could contribute to better and deeper understanding of human health and behavior across the lifespan. More specifically, the proposed research has 4 core aims. First, we plan to test the hypothesis that early life stress (birth to 5 years), indexed by exposure to psychological stressors (e.g., maltreatment, separation, caregiver depression) at different points during development, leads individuals to: (a) be more stress-reactive in response to difficult/challenging situations in adulthood (i.e., dysregulated HPA-axis activity), and (b) experience more inflammation (i.e., indexed by C-reactive protein and interleukin-6). The results are expected to be most pronounced when "vulnerable" individuals (i.e., adults who experienced greater psychological stress early in life) report greater concurrent stress in adulthood, with the statistical interaction of greater early life stress and greater current stress predicting the most stress reactivity and inflammation in adulthood. Second, we plan to test the hypothesis that adult health biomarkers (i.e., HPA-axis stress-reactivity and inflammation) are the link between certain types of early life stress and negative health problems in adulthood (e.g., asthma, hypertension, obesity, depression). Again, the results are expected to be strongest when "vulnerable" individuals experience higher levels of current stress in adulthood, with the statistical interaction of greater early stress and greater current stress predicting the most deleterious health problems in adulthood. Third, we plan to test whether this proposed developmental model provides a better fit to the data than competing models, including: (1)"early life stress only", (2) "current life stress only", (3) "adolescent and current life stress", and (4) "cumulative stress". The model comparisons will examine the influence of the timing of life stress on adult health, testing the hypothesis that certain types of early life stress sensitize systems associated with stress reactivity in response to subsequent negative events that, in turn, affect adult health outcomes. Although cumulative life stress from birth to middle adulthood should be the best predictor of negative health outcomes, the proposed model of early and current life stress is expected to predict outcomes better than models of early stress only, current stress only, or adolescent and current stress. Finally, we plan to test important moderating influences on the relations between early life stress, adult health indexes (biomarkers), and adult health outcomes. Potential moderators include early caregiving quality (i.e., observed parental sensitivity, responsiveness, and overall quality from birth to age 4 years), quality of parent- child social support (i.e., partner, family, friendship support) from the participant's birth to age 17, and participant's social support (i.e., partner, family, friendship support) from ages 19 to 32. We believe that modeling and documenting the hypothesized health-related trajectories will result in a more integrated and nuanced understanding of human health and behavior from birth to middle-age.